Telomere Shortening: Causes and Effects

Telomere Shortening: Causes and Effects Harry McLellan Introduction Telomeres are a repeating sequence TTAGGG, a couple thousand nucleotides long (Kim, et al, 1994) at the end of chromosomes that prevents the degradation of DNA and stops the ends of chromosomes binding together as well as preventing unnecessary repair. The main function of telomeres is preservation of DNA. During cell replication there is a shortening of the telomeric sequence with each cell division (Kim, et al, 1994). Once telomeres become short enough, approaching a critical length the cell begins senescence (Blasco et al. 1997). Therefore, it has been suggested telomere length produces a mitotic clock which could predict cell and organism death (Harley, 1991). Telomeres degrade naturally with each cell division but certain lifestyle factors may accelerate degradation and negatively affecting the health and fitness of an individual. This literature review will explore how telomere length is affected by lifestyle factors and ultimately how this has an effect on ageing. This literat ure review will specifically focus on the telomere length and aging process in humans. A subject gathering a lot of attention and understanding in recent years with the power to predict the longevity of an organism and opportunities to reduce the aging process. Structure and function of telomeres Telomeres cap the ends of chromosomes (Fig. 1) and protected the connected DNA sequences during cell division. Figure 1 a schematic of the end DNA replication problem and how base pairs are lost. Retrieved online at: http://senescence.info/telomeres_telomerase.html (viewed on 18/03/2017)       When the cell divides, DNA must be replicated. However, because DNA can only be replicated 5 to 3, the lagging strand is replicated through backwards stitching. While the leading strand is replicated continuously, the lagging strand requires RNA primers, which provide 3 hydroxyl groups to build from. Then once the primers are removed, a gap is left at the extreme end of the lagging strand template. To stop chromosomes shortening, the end of the DNA strand is a repeating sequence (a telomere) recognised by an enzyme telomerase, which fills in the missing nucleotides to complete the template and ensure no information is lost (Klapper et al. 1998). While telomerase activity is detected in cells with high proliferation potential, in somatic cells it is virtually undetected resulting in the overall shortening of telomeres with each cell division. In immortal or cancerous cells however, telomerase activity is reactivated providing the basis for unregulated and potentially infinite division s as telomere length is repaired after division (Dunham et al. 2000). Figure 2 human chromosomes (grey) capped with stained telomeres (white) retrieved online at: http://science.nasa.gov/media/medialibrary/2006/03/16/22mar_telomeres_resources/caps.gif (viewed on 11/03/2017) Effects of shortening It might be possible to predict a cells lifespan by measuring telomere length, an experiment using cultured human liver tissue reported results of 29-60 base pair loss per year (Takubo et al. 2000). Jiang et al. (2008) and Song et al. (2010) measured the levels of stathmin and EF-1a, which mark DNA damage and dysfunction and found that there is a steady increase with increasing age in humans. Resulting in the overall negative relationship with telomere length and age. Cawthon et al. (2003) found certain genetic disorders like dyskeratosis congenital, the progressive failure of bone marrow leading to early mortality can accelerate telomere shortening. Whilst normal cells loose telomere fragments with each cell division, sufferers of dyskeratosis congenital will experience premature deaths and early development of age related diseases. The same study also compared people of the same age group and lifestyle and found those with naturally shorter telomeres where likely to suffer from a wide range of diseases and had poor survival. Without being affected by life factors, telomere length changes between individual and can give an indication to the life span. Shorter telomeres can lead to genome instability and a higher risk of genetic disease. Gender, genetics and disease In humans there is a negative correlation between telomere length and age, Valdes et al. (2005) published a study that looked at one thousand women and concluded that the human telomere sequence is depleted by 27 base pairs a year by measuring the mean TRF (telomere restriction factor) length using a Southern blot method. Brouilette et al. (2003) found there was no significant difference in telomere shortening rates or length between males and females. Inherently, telomeres can be short and when shorter than average the individual becomes at risk of disease and a reduced lifespan (Farzaneh et al. 2008; Cawthon et al. 2003). Cardiovascular disease is commonly associated with short telomeres (Yang et al. 2009). Telomere length can also be affected by environmental factors (Steinert et al. 2004) not just genetic factors. Factors such as body mass, diet, smoking and exercise (Valdes et al. 2005; Cherkas et al. 2008) all cause a decrease in telomere length and eventual cell senescence (Stiewe and Pà ¼tzer 2001). Factors like smoking and poor diet will accelerate telomere shortening and lead to disease development. Coronary heart disease associated with short leukocyte telomeres (Brouilette   et al. 2003), increased risk of mitochondrial diseases (Zee et al. 2009), atherosclerotic diseases (Van der Harst et al. 2006), diabetes (Sampson et al. 2006) and increased risk in various cancers (Wu et al. 2003). In summary gender has no effect on telomere length but short telomeres are linked to a variety of cancers and disease. Cancer When telomere length becomes too short, the telomere can be subject to repair or recombination (Klapper, et al, 1998). De Lange (2005) published findings that repaired lesions are the probable cause of a cell turning cancerous. In conjunction with this Meeker (2006) stated that short dysfunctional chromosomes are involved in carcinogenesis. Using laser capture microdissection Shammas et al. (2008) looked at the function of telomeres and telomerase activity in adenocarcinoma (types of tumour) cells and found that when telomeres reach a critically short length telomerase activity increases. The same study also found when telomerase activity is suppressed the tumour cells did not proliferate; highlighting telomeres and telomerase involvement in cancerous cells. Poor diet and smoking Telomere shortening to a critical length can cause damage to the genome and potentially turn cancerous. Long term smoking is linked to carcinogenesis in cells (Valdes et al. 2005). Telomere length in circulating lymphocytes is show to be significantly shorter in long term smokers compared with the control none smokers. The exposure to tobacco has a negative effect on the telomere length and accelerates shortening (Morla, 2006). Using biomarkers accumulative DNA damage can be monitored. During ageing and or obesity there is a significant increase in biomarkers human blood. Smoking also caused there to be an increase in biomarkers (Song et al. 2010). When analysed telomeres shorten by roughly 27 base pairs a year but with introduction of smoking 20 cigarettes a day, around 31 base pairs are lost (Valdes et al. 2005); an overall detrimental effect on telomere length. In conjunction with this Epel et al. (2004) produced a study on oxidative stress linked to smoking and telomeres and resu lts showed cells under high oxidative stress had lower levels of telomerase activity and were more susceptible to telomere shortening, aiding the ageing process. Overall smoking has a negative effect and accelerates shortening of telomeres, which can lead to development of tumours or cell death (Meeker, 2006). Oxidative stress is linked with telomere shortening, which leads to DNA damage or premature cell death (Epel et al. 2004). Another factor that increases oxidative stress is poor diet and obesity. A study on obese mice (Furukawa, 2004) showed a positive correlation between fat accumulation and increase in oxidative stress. The study also introduced a NADPH oxidase inhibitor which caused a reduction in adipose tissue (fat/ loose connective tissue) highlighting that fat accumulation is directly linked to oxidative stress. The study concluded with the introduction of the NADPH oxidase inhibitor, caused the conditions of the mice to improve. The reduction in oxidative stress also reduces the telomere shortening (Valdes et al. 2005) and reducing damage to the genome. In summary an increase in oxidative stress has a negative impact on telomere length and ageing. Stress and environment Lifestyle choices impact telomeres length and so does environment an individual lives or works in. A study was conducted to look at the airborne pollutants like toluene and benzene within a city that humans are exposed to on a daily bases (Hoxha et al. 2009). 77 traffic officers and 57 office workers had blood samples taken that where later analysed using real time PCR. Hoxha et al. (2009) analysed the leukocyte telomere length and found a significant difference. Traffic officers who are exposed to traffic pollutants had shorter telomere length compared to office workers. Exposure to pollutants increases telomere shorting and risk from disease and ageing. In conjunction to this Pavanello et al. (2010) studied the leukocyte telomere length in 48 coke over workers compared to 44 controls. All none smokers and all in the same age group the coke oven workers are exposed to polycyclic aromatic hydrocarbons on a daily basis. Pavaello et al. (2010) concluded that coke oven workers exhibited a significantly shorter leukocyte telomere length and higher genome instability linked with disease and ageing (Farzaneh et al. 2008; Cawthon et al. 2003). When an individual becomes stressed, the adrenal steroid glucocorticoid is released. Glucocorticoid has the potential the increase oxidative stress as it is known to inhibit the activity of glutathione peroxidase (an antioxidant enzyme) (Patel et al. 2002). In rats corticosterone (adrenal steroids in rats) caused a decrease in NADPH which is an oxidase inhibitor, (Furukawa, 2004) leading to an increase in oxidative stress and telomere shortening. Stress is associated with oxidative pressure, which is linked to shorter telomeres and poor health. Epel et al. (2004) took a group of women who perceived to have a lot of stress in their life and compared them to a control group who had little stress in their life. The participants consisted of 58 mothers, 19 whom had healthy children and 39 who had chronically ill children. The women with chronically ill children where perceived to have a higher level of stress in their life. The study on shortening in response to stress concluded that women who have a high amount of perceived stress in their life had shorter telomeres equivalent to that of a decade of ageing compared to their control counterparts (Epel et al. 2004). Stress negatively affects telomere length and can lead to poor health and development of disease. Antioxidants Two groups of women and their dietary intake where monitored over the course of five years. The study looked at diets containing high amount antioxidants, mainly vitamin C and E rich foods (fish, fruit and vegetables) against diets which did not (Farzaneh-Far et al. 2008). By measuring telomere length, using quantitative PCR and monitoring the levels of fatty acids in blood, Farzaneh-Far et al. (2008) concluded that an increase in antioxidants correlated with a reduction in shortening of telomeres and the women participants with regular antioxidant intake generally had longer telomeres in comparison to the other dietary group. In a similar study involving 1,067 cases and 1,100 controls, the dietary intake of antioxidants is recorded to study its involvement with the development of breast cancer in women (Shen et al. 2009). In correlation to Farzaneh-Far et al. (2008), Shen et al. (2009) found the same link of a reduction in telomere shortening with increase in antioxidants in the die t. The same paper revealed women with poor diet and low antioxidant intake were far more at risk of developing breast cancer. Antioxidant reduce oxidative damage and telomere shortening. Oxidative stress and nutrition restriction Oxidative damage increases telomere shortening and telomeres are linked to cell senescence. Oxidative damage is therefore linked to the longevity of an organism (Jennings et al. 2000). Dietary restrictions have been placed on organisms such as rats to test whether a decrease in nutrition will decrease oxidative damage. Jennings et al. (2000) found that when nutrition is decreased so that optimal growth cannot be sustained there is an increase in longevity and this is true for a large range or organisms. In an earlier study, Jennings et al. (1999) made the link between early growth and shortened kidney telomeres in rats in later life. The rats with diet restrictions had a reduced maternal growth followed by a postnatal growth catch up but had longer kidney and liver telomeres, which are associated with increased longevity of up to 15% (Jennings et al. 1999). To summarise telomere shortening is accelerated by oxidative stress which in turn can be reduced by nutrition restrictions which will increase longevity. Exercise Oxidative stress from poor diet and general perceived stress can cause an acceleration in telomere shortening (Epel et al. 2004; Farzaneh-Far et al. 2009). Exercise can reduce the effects of stress shortening. Two groups of mice where placed into containers. A group given the option to exercise on a running wheel and the other group given no option to exercise. All running done was voluntary. At the end of the experiment, the mice given the option to exercise showed an increase in telomere stabilisation proteins and a suppression of cell apoptosis regulators (Werner et al. 2009). When tested on humans similar results occurred. When track and field athletes are compared to untrained individuals the data obtained showed an increase in expression of telomere stabilisation proteins in athletes and reduced leukocyte telomere shortening (Werner et al. 2009). Regular exercise will supress the effects of stress and reduce the effects of ageing by preservation of telomeres.    Conclusion Telomeres naturally shorten with time and are reflected in the aging of a human. A cell can only divide so many times before the genome becomes damaged (Klapper, et al, 1998), in this instance the cell must begin cell senescence or apoptosis. Many lifestyle factors like obesity, smoking, poor diet, genetic inheritance, pollution, and stress can accelerate telomere shortening and ageing causing premature death or disease. Other factors work the opposite way, consumption of antioxidants can reduces oxidative stress and slow down telomere shortening (Farzaneh-Far et al. 2008). Regular exercise can increase expression of telomere stabilising proteins (Werner et al. 2009). Restricting nutrition to limit optimal growth will increase the longevity of an organism (Jennings et al. 2000). Telomere length analysation using quantitative PCR can be used to predict the lifespan of an organism and help stop the onset of premature age related diseases.